Summary/Abstract Between 3-4 million Americans, mostly men, have used anabolic-androgenic steroids (AAS) illicitly to increase muscularity. There are nearly 100,000 new AAS users each year and more than 30% of AAS users, or about 1 million men, have developed AAS dependence, among the highest dependence rates of all abused drugs. Emerging data from our group and others indicate that long-term AAS use impairs memory, alters brain structure and chemistry, induces abnormal androgen levels and increases excess oxidative stress, effects similar to those found in people diagnosed with or who develop Alzheimer?s Disease and its related dementias (AD/ADRD). The abnormally high and low androgen levels experienced by AAS users when taking and abstaining from AAS, respectively, induce excess oxidative stress. Chronic high or low androgen levels or excess oxidative stress increase the production of and reduce the elimination of beta-amyloid and hyperphosphorylated Tau (Tau-P) proteins, thereby increasing beta-amyloid and Tau-P burdens. Thus, a strong scientific premise supports our hypothesis that nearly 1 million AAS-dependent men are at increased risk for developing AD/ADRD as they age. In spontaneous AD/ADRD, beta-amyloid burdens begin to increase at about age 40. We hypothesize that AAS use, which begins at a median age of 22, initiates beta-amyloid and Tau-P protein increases nearly 2 decades earlier than would occur naturally, resulting in higher beta-amyloid and Tau-P burdens in middle-aged AAS users. This Administrative Supplement to R01DA041866-01A1 seeks support to assess, for the first time, whether long-term AAS users have elevated brain beta-amyloid and Tau-P burdens, using Positron Emission Tomography of [11C]-Pittsburgh compound B and [18F]-Flortaucipir, respectively. Brain beta-amyloid and Tau-P burdens in AAS users will be compared to burdens in healthy controls on file matched for age and other demographic factors. Additionally, using cognitive testing and magnetic resonance spectroscopy procedures that are part of our parent R01, we will assess whether beta- amyloid and Tau-P burdens in AAS users are associated with visuospatial memory performance and anterior cingulate scyllo-inositol levels, the former of which predicts development of AD/ADRD and the latter of which reduces beta-amyloid burdens, to determine whether memory performance and scyllo-inositol levels predict beta-amyloid or Tau-P burdens. The resulting data will either refute our hypothesis or form a foundation that supports future studies of beta-amyloid and Tau-P burdens in AAS users. Since hypogonadism and excess oxidative stress occur as a consequence of normal aging in men and in women, and because both conditions can be mitigated by existing therapies and by newer more potent antioxidants, the data we obtain could lead to new ways to diagnose or treat AD/ADRD in the general population as well as in AAS users.